Leukotrienes constitute a group of locally functional hormones produced from arachidonic acid in vivo and major leukotrienes include leukotriene B4 (LTB4), C4 (LTC4), D4 (LTD4) and E4 (LTE4). The biosynthesis of the leukotrienes involves the production of an epoxide known as leukotriene A4 (LTA4) from arachidonic acid by the action of 5-lipoxygenase, and LTA4 is then converted to various leukotrienes through a series of enzymatic steps (see Leukotrienes and lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam, 1989).
Recently, montelukast or its pharmaceutically acceptable salt is known to function as an antagonist and also as a biosynthesis inhibitor against leukotrienes. The sodium salt of montelukast is commercially available from Merck under the trademark of Singulair® for treating asthma.
EP 480,717 discloses a method of preparing said montelukast sodium salt: As shown in Reaction Scheme 1, methyl 1-(mercaptomethyl)cyclopropylacetate of formula (B) is coupled with the compound of formula (A) to produce the compound of formula (C) as an intermediate, and the compound of formula (C) is then hydrolyzed to obtain the free acid form thereof, followed by treating the free acid with NaOH. However, this method gives a low yield or the manufacturing cost is high.
THP: tetrahydropyranylPPTS: Pyridinium p-toluenesulfonate
In order to solve the above-mentioned problems, EP 737,186 suggests a method as shown in Reaction Scheme 2. This method uses a methanesulfonyl compound of formula (A′) having an unprotected hydroxyl group instead of the THP-protected compound of formula (A). Further, this method uses 1-(mercaptomethyl)cyclopropylacetate dilithium salt of formula (B′) instead of methyl 1-(mercaptoethyl)cyclopropylacetate of formula (B), thereby making the subsequent deprotection step unnecessary. Subsequently, dicyclohexylamine is added to the compound of formula (C″) to produce the compound of formula (D), which is converted to the desired sodium salt.

However, the methanesulfonyl compound of formula (A′) used in the above process as a starting material is very unstable, which makes the whole process very complicated. Namely, the reaction to produce the compound of formula (A′) must be performed at a low temperature of about −30° C. and the product is required to be kept at about −15° C. The compound of formula (A′) thus produced is unstable toward moisture and air, and therefore, the reaction thereof has to be conducted quickly under carefully controlled conditions. Also, the synthesis of the compound of formula (B′) requires the use of n-butyllithium which is very explosive and unstable toward moisture and air. Thus, the method described in Reaction Scheme is not suitable for large-scale production.